Decreased allopregnanolone induced by oral contraceptives is associated with a reduction in social behavior and sexual motivation in female rat

The progesterone reduced metabolite allopregnanolone is a neuroactive steroid, produced in the periphery and directly in the brain, which exerts a rapid non genomic effect on neuronal excitability through a direct modulation of the type A receptor of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain (Majewska, 1992). It has been shown that allopregnanolone facilitates social and sexual behaviour of rodents, which evoke further increases in brain allopregnanolone concentrations (Frye, 2009). Thus, systemic or local allopregnanolone administration in the hypothalamus or midbrain, promotes sexual behavior, while blocking progesterone metabolism through a 5α-reductase inhibitor, reduces proceptivity and receptivity compared to control animals (Frye et al., 1998, 2009). We have previously demonstrated that chronic treatment with a combination of ethinyl estradiol and levonorgestrel, two of the compounds most frequently used in the preparation of oral contraceptives (OCs) , once daily for 4 weeks to female rats, induces a decrease in brain and plasma concentrations of allopregnanolone and progesterone (Follesa et. al, 2002). We now examined whether the reduction in the concentrations of allopregnanolone induced by OCs was associated with a modification in the social and sexual behavior of rats. Chronic treatment with OCs (17- ethinyl estradiol + levonorgestrel per os, once daily for four weeks) specifically affects social and agonistic behavior without affecting non-social activity in the Resident-Intruder test. In fact, this treatment decreases the frequency of the dominant score (-114%), the duration and frequency of agonistic behaviors delivered (-78% and -60% respectively) and the duration and frequency of social investigation (-37% both), while increasing the duration in social inactivity (+238%). Moreover, chronic OCs administration significantly reduces sexual motivation but not sexual activity of rats. In fact, in the Paced mating test OCs-treated rats showed no proceptive behaviours (ear wiggling, hops and darts), while the receptivity, measured as lordosis quotient (LQ, number of lordosis / male mount + intromissions x100), was not significantly affected. Progesterone administration (4 mg/kg, s.c.) 4 h before the Paced Mating test significantly increases proceptivity in animals treated with OCs. Administration of finasteride (50 mg/Kg, sc, 2 hours before progesterone), a 5-reductase inhibitor that decreases allopregnanolone concentrations, almost completely abolishes this effect (-75%). These results demonstrate that the decrease in allopregnanolone concentrations induced by OCs is associated whit a decrease in social behaviors and with a reduced sexual motivation in rats. These effects might be relevant to the side effects some-times exhibited by women taking OC pills.